Synovial sarcoma (SS), an often lethal sarcoma occurring predominantly in young adults, is defined by a specific chromosomal translocation, t(X;18), which fuses the SYT gene on chromosome 18 to either the SSXl or the SSX2 gene on chromosome X. The SYT-SSX fusion oncoprotein functions as aberrant transcriptional protein that SYT-SSX exerts its transcriptional effects by interacting with histone-modifying enzymes, leading to a deregulation of epigenetic control of gene expression. The present proposal brings together expertise in fundamental histone code biology with experience in synovial sarcoma cell line- and human tissue-based translational research to develop a deeper understanding of SYT-SSX-dependent histone code alterations that could lead to more rational, more precisely targeted, and, hopefully, more effective epigenetic therapy for synovial sarcoma. The proposed work addresses the central role of SYTSSX- dependent epigenetic alterations in the biology of synovial sarcoma from three complementary perspectives: mechanistic (Aim 1), global genomic (Aim 2), and preclinical (Aim 3). Certain cancers are thought to arise from genetic rearrangements that join separate genes to produce new fusion genes with abnormal functions. The SYT-SSX fusion gene in synovial sarcoma is such a gene. Understanding and targeting the biological mechanisms used by these cancer-causing fusion genes can lead to effective therapeutics, as exemplified by imatinib targeting BCR-ABL in chronic myelogenous leukemia and all-trans retinoic acid targeting PML-RARa in acute promyelocytic leukemia.